The chromatin remodeling protein BRG1 regulates APAP-induced liver injury by modulating CYP3A11 transcription in hepatocyte

Acetaminophen (APAP) overdose represents the most frequent cause of acute liver failure. The underlying epigenetic mechanism is not fully understood. In the present study we investigated the mechanism whereby the chromatin remodeling protein brahma related gene 1 (Brg1) regulates APAP induced liver injury in mice. We report that hepatocyte-specific deletion of Brg1 attenuated APAP induced liver injury in mice as evidenced by reduced plasma ALT and AST levels, decreased liver necrosis, amelioration of GSH depletion, and prolonged survival. Brg1 regulated APAP-induced liver injury likely by stimulating the transcription of Cyp3a11, a key cytochrome enzyme involved in APAP metabolism. Immunoprecipitation coupled with DNA affinity microarray identified hepatocyte nuclear factor 4 (HNF4) as a novel binding partner for Brg1. HNF4 recruited Brg1 to the Cyp3a11 promoter and formed a complex with Brg1 to trans-activate Cyp3a11. In contrast, BRG1 deficiency attenuated HNF4 binding to the Cyp3a11 promoter and dampened Cyp3a11 transcription. Therefore, our data suggest that Brg1 might play an essential role mediating APAP induced liver injury in vivo.